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Department of Biochemistry, Michigan State University, East Lansing, MI 48824
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT Link between immune integrity...Prevalence of deficiencies in...Role of glucocorticoids in...Impact of zinc deficiency...Changes in lymphopoiesis created...Potential resistance of myeloid...Role of zinc status...Ability of zinc to...Impact of zinc supplementation...Important areas of needREFERENCES |
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KEY WORDS: • apoptosis • immune response • lymphopoiesis • zinc deficiency
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Link between immune integrity and nutritional status |
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TOPABSTRACTLink between immune integrity...Prevalence of deficiencies in...Role of glucocorticoids in...Impact of zinc deficiency...Changes in lymphopoiesis created...Potential resistance of myeloid...Role of zinc status...Ability of zinc to...Impact of zinc supplementation...Important areas of needREFERENCES |
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, Endre et al. 1990
). Early studies
made it clear that suboptimal nutriture associated with an inadequate
diet or with the many diseases in which nutritional status is altered
could significantly impair host defense systems (Keen and Gershwin 1990
). As cancer, acquired immune deficiency syndrome
(AIDS),4
renal and gastrointestinal diseases and
other diseases advance, wasting and impaired host defense go hand in
hand (Endre et al. 1990
). These diseases, as well as
suboptimal diets, create heightened incidences of opportunistic
infections, sepsis, pneumonia and so on, which also increase morbidity
rates in affected subjects (Chandra and Newberne 1977
,
Endre et al. 1990
). Early human studies provided the
first evidence that nutritional status and immune status were tightly
linked, and recent data collected in mouse models affirm this
relationship (Endre et al. 1990
, Fraker et al. 1993
). Perhaps the best developed nutritional-immunological
paradigm is the zinc-deficient mice, in which the impact of
a single nutritional element on the immune system could be probed in
depth. The collective data, which are reviewed here, indicate that as
zinc becomes suboptimal, its impact on the immune system is rapid and
extensive, being far greater than its impact on other tissues and
organs (Fraker et al. 1993
). Indeed, the impact of zinc
deficiency on the immune system of the young adult mouse was of such
intensity that for some time it was difficult to understand. Also
addressed is a better understanding of why the ties between zinc status
and immune status are so interrelated. For three decades, the hallmarks of malnutrition, especially of protein-calorie deficiencies (PCM) and zinc deficiency, were thymic atrophy and lymphopenia. The underlying mechanisms that create these two major changes in immune integrity are now documented and provide new insights into how nutritional deficiencies change the composition of the peripheral immune system and the regulation of hematopoiesis. The ability of zinc supplementation to offset the changes in immune function created by malnutrition and disease is also addressed.
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Prevalence of deficiencies in zinc among humans |
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TOPABSTRACTLink between immune integrity...Prevalence of deficiencies in...Role of glucocorticoids in...Impact of zinc deficiency...Changes in lymphopoiesis created...Potential resistance of myeloid...Role of zinc status...Ability of zinc to...Impact of zinc supplementation...Important areas of needREFERENCES |
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, Fraker et al. 1993
, Keen and Gershwin 1990
). In the United
States, suboptimal intake of dietary zinc has been observed in children
from low income families, low birth weight infants, frail elderly
persons, children with chronic diarrhea and some pregnant teenagers
(Endre et al. 1990
, Sazawal et al. 1998
).
Acrodermatitis enteropathica, a genetic disorder affecting the
assimilation of zinc, occurs in the human population although at an
infrequent rate (Endre et al. 1990
). Although data were
collected in the late 1970s, it is evident from Table 1
that host defense was indeed altered in patients with acrodermatitis
enteropathica (Anonymous 1981
). This genetic disease was
one of the first to provide the hallmarks of zinc deficiency, i.e.,
thymic atrophy and lymphopenia. Decreased cell-mediated responses
and an increased incidence of infections were also noted in these
patients.
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, Chandra and Newberne 1977
, Endre et al. 1990
, Fraker et al. 1993
, Keen and Gershwin 1990
). Examples of the
impact of several of these conditions on zinc and immune status are
shown in Table 2
. Prasad and coworkers (Kaplan et al. 1988
) found
defective natural killer (NK) function and anergic delayed type
hypersensitivity (DTH) responses in patients with sickle cell anemia
who had only modest depletion of serum zinc. Prolonged tube feeding
created a zinc-deficient subject with lymphopenia and reduced NK
responses (Allen et al. 1983
). Elderly persons present a
mixed picture with regard to zinc status; however, decreased
interleukin-2 (IL-2) production and lymphopenia were noted in
individuals with marginal zinc status (Kaplan et al. 1988
). A subset of human immunodeficiency virus–positive
patients exhibit deficiencies in zinc and selenium that correlate with
reduced host defense and higher rates of morbidity (Baum et al. 1995
). Although these studies provide useful
information, they are typical of human studies in which immune
assessments are limited in scope. Nevertheless, there are a variety of
conditions in which suboptimal intake of zinc affects human health and
immune status. They deserve more extensive research, especially because
zinc supplementation might reduce the impact of these diseases and
conditions.
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, Golden et al. 1978
, Kuvibidila et al. 1993
). Low serum zinc
has been noted in children with PCM (Chandra and Newberne 1977
, Endre et al. 1990
, Golden et al. 1978
, Kuvibidila et al. 1993
), and of course,
inanition or reduced caloric intake accompanies zinc deficiency
(Luecke et al. 1978
). The parallels continue between
zinc deficiency and PCM because both cause thymic atrophy, lymphopenia
and impaired cell- and antibody-mediated responses in humans,
mice and primates (Chandra and Newberne 1978, Fernandes et al. 1979
, Fraker et al. 1993
, Golden et al. 1978
, Keen and Gershwin 1990
, Kuvibidila et al. 1993
,
Luecke et al. 1978
). As mentioned, increases in sepsis,
pneumonia, flu, Candida and other types of infections are
noted in PCM and zinc-deficient subjects (Chandra and Newberne 1978, Endre et al. 1990
, Fraker et al. 1993
, Keen and Gershwin 1990
,
Kuvibidila et al. 1993
). Indeed, the two deficiencies,
although not identical, have many common features (Table 3
).
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Role of glucocorticoids in the alteration of immune defense for zinc and protein-calorie deficiencies |
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TOPABSTRACTLink between immune integrity...Prevalence of deficiencies in...Role of glucocorticoids in...Impact of zinc deficiency...Changes in lymphopoiesis created...Potential resistance of myeloid...Role of zinc status...Ability of zinc to...Impact of zinc supplementation...Important areas of needREFERENCES |
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, Becker 1983
, DePasquale-Jardieu and Fraker 1979
, 1980
, Smith et al. 1981
). Moreover, these early experiments that indicate a
decline in zinc status caused significant changes in endocrine function
were important in our current understanding of the secondary
physiological changes created by zinc deficiency and of their impact on
the immune system, especially lymphopoiesis (DePasquale-Jardieu and Fraker 1979
, 1980
). These endocrine changes
also provide part of the basis for assigning a major role to apoptosis
in the loss of precursor lymphocytes during zinc deficiency, as
discussed. |
Impact of zinc deficiency on the immune system: Mouse models |
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TOPABSTRACTLink between immune integrity...Prevalence of deficiencies in...Role of glucocorticoids in...Impact of zinc deficiency...Changes in lymphopoiesis created...Potential resistance of myeloid...Role of zinc status...Ability of zinc to...Impact of zinc supplementation...Important areas of needREFERENCES |
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). Our
laboratory and others found that as little as 30 d of zinc
deficiency reduced cell-mediated, DTH, tumor defense and
antibody-mediated responses by ~30–80% depending on the degree
of deficiency (Fernandes et al. 1979
, Fraker et al. 1993
, Keen and Gershwin 1990
). Challenging
zinc-deficient mice with subacute levels of infectious
agents such as Trypanosoma cruzi or nematodes resulted in
death due to impaired defense (Fraker et al. 1982
,
Shi et al. 1998
). Thus, the essentialness of zinc to the
integrity of the immune system was made very clear by these studies!
Nevertheless, the rapid impact of zinc deficiency on the murine immune
system was surprising. When body weight losses were 24 and 32%,
researchers observed 50 to 80% losses in thymus weight and 40
to 80% losses in antibody-mediated responses and so on
(Cook-Mills and Fraker 1993
, Fraker et al. 1993
). The losses in defense capacity closely correlated with
losses in absolute numbers of peripheral lymphocytes and splenocytes.
Thus, zinc-deficient mice with half the number of splenocytes
produced about half the number of antibody-producing cells as
normal mice (Cook-Mills and Fraker 1993
, Fraker et al. 1993
). Earlier studies indicated that on a per-cell
basis, the residual splenocytes of zinc-deficient mice produced
normal amounts of antibody and IL-2 and responded well to a battery of
mitogens (Cook-Mills and Fraker 1993
, Dowd et al. 1986
). More recent work using zinc-deficient weanling mice,
however, showed deficient production of IL-4, IL-5 and so on
(Shi et al. 1998
), although we noted no changes in the
phenotypic distribution (composition) of the various subsets of T and B
cells in the spleen (King and Fraker 1991
, Shi et al. 1998
). Collectively, these studies suggested that changes
in the production of lymphocytes (lymphopoiesis) might be a seminal
cause of lymphopenia that would in turn reduce cell- and
antibody-mediated responses. However, there has never been an
extensive study of the effects of a nutritional deficiency on
lymphopoiesis or myelopoiesis.
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Changes in lymphopoiesis created by zinc deficiency: emerging role for apoptosis |
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TOPABSTRACTLink between immune integrity...Prevalence of deficiencies in...Role of glucocorticoids in...Impact of zinc deficiency...Changes in lymphopoiesis created...Potential resistance of myeloid...Role of zinc status...Ability of zinc to...Impact of zinc supplementation...Important areas of needREFERENCES |
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, Fraker et al. 1995
).
Adrenalectomies also protected the thymus from atrophy in PCM mice
(Wing et al. 1988
). This increased our suspicions that
zinc deficiency was altering the production of lymphocytes. However,
the fact that endogenously induced Gc might play a significant role in
the demise of a segment of the immune system was not a popular concept
with some colleagues, who preferred that everything be more directly
linked to zinc-related functions. These results remained in the
background until it became evident in the 1980s that Gc were a classic
inducer of apoptosis in thymocytes or precursor T cells (Cohen and Duke 1984
, 1992
). Subsequently, it was also
shown that in vitro deprivation of serum could induce apoptosis in
thymocytes, which seemed to us to be a facsimile for zinc deficiency
and PCM (Cohen and Duke 1992
). Thus, it also seemed
probable that the combination of suboptimal zinc and chronic elevation
of Gc might be causing the apoptotic elimination of precursor B and T
cells in the marrow and thymus that would lead to lymphopenia
(Fraker et al. 1993
).
However, no one had shown that the precursor B cells and other
progenitor cells in the marrow were susceptible to Gc-mediated
apoptosis because of the lack of available methodology. One could not
hope to purify sufficient precursor B cells (8–14%) (Hardy et al. 1991
) to evaluate for apoptosis using DNA gels
(semiquantitative) or morphology (laborious). Fortunately, the flow
cytometer can be used to readily quantify apoptotic cells in a
population (Telford et al. 1994
). By using multicolor
flow cytometry with fluorescently labeled antibodies specific for
progenitor and precursor B-cell markers along with a DNA dye, it
was shown that precursor B cells were as prone to Gc-induced
apoptosis as were thymocytes. Moreover, they responded intensely both
in vitro and in vivo to levels of steroid analogous to those found in
zinc deficiency and PCM (Garvy et al. 1993a
and
1993b
). It was subsequently shown that B cells from the
bone marrow of human subjects were equally sensitive to these steroids,
making the phenomenon relevant to human health (Lill-Elghanian,
D., Schwartz, K., King, L. and Fraher, P., unpublished data).
After having this methodology in hand, the next step was to demonstrate
that zinc deficiency rapidly depleted the B-cell compartment of the
marrow (Fraker et al. 1995
, King et al. 1995
). Recent work showed that zinc deficiency caused a
50–70% decline in precursor B cells
(B220+CD43-IgM-),
with somewhat similar declines noted for immature B cells
(B220+IgM+IgD-)
(King et al. 1995
, Osati et al. 1998
).
Conversely, pro-B cells
(B220+CD43+6C3+)
exhibited no change in their distribution, gradually becoming a greater
proportion of the marrow as the compartment was depleted of precursor
and immature B cells (Osati et al. 1998
). Mature B cells
(IgM+IgD+) were also fairly
resistant to zinc deficiency. The explanation appears to be that
pro-B cells, which are just beginning gene rearrangements and are
not yet a problem or a threat, all express higher levels of bcl-2 than
precursor B cells and thus are more protected against apoptosis created
by zinc deficiency (Merino et al. 1994
). When expressed
at high levels, bcl-2 is a proto-oncogene that can block a variety
of death cues (Mignotte and Vayssier 1998
). Conversely,
because precursor B cells have a >90% chance of generating nonsense
clones and must be eliminated apoptotically (a few percent also became
anti-self clones), their expression of bcl-2 is quite low
(Merino et al. 1994
). Mature B cells, on the other hand,
which have made acceptable rearrangements, also express high levels of
bcl-2. Thus, the pattern of survival of B cells during zinc deficiency
paralleled bcl-2 expression and suggests that apoptosis is indeed a
component of the zinc deficiency–induced depletion of the B-cell
compartment. Nevertheless, because apoptotic cells are quickly
phagocytosed, it has been difficult to directly prove that precursor T
and B cells are eliminated apoptotically in the zinc-deficient
mouse. Evidence provided by other laboratories indicate that zinc
deficiency causes apoptosis in embryos and enhances DNA strand breaks
in zinc-deficient infant rhesus monkeys (Olin et al. 1993
, Rogers et al. 1995
) and that calorie
restriction can also enhance apoptosis (Luan et al. 1995
). Apoptosis clearly plays a role in nutritional
deficiencies that must be better understood.
Thus, it is becoming evident that zinc deficiency has a substantial and rather specific impact on the lymphocytic branch of the immune system. The rapid depletion of the marrow and the thymus of precursor T and B cells as zinc deficiency advances reduces the ability of the immune system to replenish the peripheral blood and secondary immune tissues with adequate numbers of lymphocytes. Thus, a significant factor in the thymic atrophy and lymphopenia that accompany zinc deficiency is an alteration in the production of lymphocytes and loss of precursor cells via an apoptotic mechanism. Therefore, a reduced ability to replenish the lymphocyte population by the primary tissues of the immune system is a key player in the observed lymphopenia that reduces host defense. The rapid and dramatic decline in the proportion of precursor T and B cells in the marrow and thymus is another clear example of the tight link of segments of the immune system to zinc status.
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Potential resistance of myeloid cells |
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TOPABSTRACTLink between immune integrity...Prevalence of deficiencies in...Role of glucocorticoids in...Impact of zinc deficiency...Changes in lymphopoiesis created...Potential resistance of myeloid...Role of zinc status...Ability of zinc to...Impact of zinc supplementation...Important areas of needREFERENCES |
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50% increase in the Mac-1–positive
population in the marrow of zinc-deficient mice that would include
cells of the myeloid series such as neutrophils,
macrophages-monocytes, basophils, eosinophils and others
(King et al. 1995
). It is important to remember that
these cells are the first line of defense, providing protection against
most pathogens and malignant and aging cells. They are at work at all
times and require the assistance of lymphocytes only if overwhelmed.
Unlike precursor lymphocytes, the early myeloid cells appeared to
survive during zinc deficiency (Fraker and King 1998
).
As the lymphocyte compartment became depleted, the neutrophil
compartment increased by as much as 40% in the marrow of
zinc-deficient mice, with even greater increases noted in the
monocytic compartment (Fraker and King 1998
).
Interestingly, there is precedence for this. Human neutrophils exposed
to Gc in vitro not only survived but also had an extended half-life
(Liles et al. 1995
, Meagher et al. 1996
).
Could this also occur in the zinc-deficient mouse? It would
constitute another mode for conserving zinc because turnover of the
neutrophils would be reduced. Moreover, immunologists have known for
years that if they want to promote myelopoiesis in in vitro cultures,
they need only add a small amount of corticosterone
(Dexter et al. 1977
). Thus, this important discovery
will be further evaluated to determine the functional status of the
granulocytes because a number of investigators noted deficits in the
function of these cells in zinc deficiency and PCM (Chandra and Newberne 1977
, Fraker et al. 1993
, Hill et al. 1995
, Vruwink et al. 1991
, Wirth et al. 1989
). Whether myeloid cells became more resistant to
apoptosis or zinc deficiency is also important to understand.
Surprisingly, several experiments indicate that the total or absolute
number of nucleated cells remained normal in the marrow of both
moderately and severely zinc-deficient mice (King et al. 1995
, Osati et al. 1998
). Thus, it was the
composition of the marrow that changed as zinc became more limiting and
chronic levels of Gc became more prevalent. The question then arose as to whether this change in the composition of the marrow was also apparent in the peripheral immune system. Preliminary studies revealed a rather remarkable twofold to threefold increase in the proportion of neutrophils in the blood of both moderate and severe zinc deficiency. Thus, there is a clear dichotomy in the effects of suboptimal dietary zinc on lymphopoiesis versus myelopoiesis that is rather striking and may represent a purposeful regulatory change in response to zinc deficiency.
A working hypothesis emerges from these findings. As zinc becomes
limiting, choices have to be made. Collectively, the marrow may be the
largest tissue of the body. Regardless, substantial amounts of zinc are
needed to produce billions of lymphocytes each day. They are the second
line of defense and often live and die without being gainfully used in
an immune response. This and the >90% error rate in their production
(Tarlinton 1994
) make them nutritionally expensive to
maintain. As zinc deficiency advances, it seems that lymphopoiesis is
put on the chopping block to be reduced in part by Gc-mediated
apoptotic mechanisms. Conversely, myelopoiesis survives at least for a
time, perhaps to provide some basic or minimal immune protection.
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Role of zinc status in cell survival and death |
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TOPABSTRACTLink between immune integrity...Prevalence of deficiencies in...Role of glucocorticoids in...Impact of zinc deficiency...Changes in lymphopoiesis created...Potential resistance of myeloid...Role of zinc status...Ability of zinc to...Impact of zinc supplementation...Important areas of needREFERENCES |
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). For example, zinc is critical to the
function of >100 enzymes and an equal number of zinc finger–dependent
transcription factors (Hallolloran 1993
, Vallee and Falchuk 1993
). Some investigators also argue that zinc is
key to membrane integrity, although specific roles remain to be
identified (Bettger and Odell 1993
). The same can be
said for the nucleus and for chromatin, which are thought to have high
concentrations of zinc (Chester 1997
). It is evident
from the work of Chester and others that zinc is very essential to DNA
synthesis and cell proliferation (Chester 1997
,
Chester et al. 1993
). The latter may be especially
relevant to changes observed in lymphopoiesis during zinc deficiency
and is the reason one should look for potential changes in cell cycle
status of pro- and pre-B cells as well as changes in the rate of
lymphopoiesis. In the past, it was presumed that there was little free
zinc in the cell and that free cellular zinc was quickly assimilated by
metallothionein (Chester 1997
). Could there,
nevertheless, be fluxes in intracellular zinc that might influence
signaling, cell death, gene expression and so on? There is increasing
evidence that some cells have zinc pools and increasing evidence that
metallothionein can donate zinc to apoenzymes (Maret and Vallee 1998
, Palmiter et al. 1996
). There may also be
zinc chaperones, as there are copper chaperones, that will direct zinc
to specific targets (Pena et al. 1998
).
Our interest in the above information stems from our observations and
those of others that zinc itself can modulate apoptosis (Fraker and Telford 1997
, McCabe et al. 1993
,
Telford and Fraker 1995
, 1998
,
Zalewski and Forbes 1993
). It is evident that apoptosis
plays key roles in immune integrity via the elimination of
anti-self and nonsense clones and the successful killing of
aberrant target cells by cytolytic T cells (Ucker 1997
).
The number of diseases in which apoptosis plays a role grows yearly,
e.g., cancer, AIDS, ischemia, autoimmune disease, stroke and
neurodegenerative diseases, especially Parkinson’s and Alzheimer’s
diseases (Ucker 1997
, Webb et al. 1997
).
Thus, it is important to identify substances that can modulate
apoptosis, and zinc may be such a candidate. Moreover, it is our belief
that apoptosis plays important roles in the changes in embryogenesis,
reproduction capacity, growth and immune integrity brought about by
nutritional deficiencies; these must be given greater consideration,
and a better understanding of the interplay between zinc and apoptosis
is critical.
Apoptosis begins with a death signal, which could be a change in the
activity of an enzyme like protein kinase C or binding of Gc to the Gc
receptor with translocation to the nucleus and the induction of death
genes (Schwartzman and Cidlowski 1993
) (Fig. 1
). In the case of the pathway used by steroids and 
-irradiation (and,
we believe, zinc), the expression of bcl-2/bax is a checkpoint in the
pathway (Chao and Korsmeyer 1998
, Schwartzman and Cidlowski 1993
, Ucker 1997
, Webb et al. 1997
). As discussed earlier, high expression of bcl-2 generally
provides enhanced protection, whereas low levels lead to cell death
(Chao and Korsmeyer 1998
, Ucker 1997
).
bcl-2 is a family of proto-oncogenes found primarily in
hematopoietic cells whose exact function is not yet known (Chao and Korsmeyer 1998
, Schwartzman and Cidlowski 1993
). There is growing evidence that it is associated with
pores in the mitochondrial membrane. When highly expressed, bcl-2 may
prevent the opening of the mitochondria pores and the release of
cytochrome c into the cytoplasm, which activates proteases
or caspases, an intermediary event in the death cascade
(Mignotte and Vayssier 1998
). There also are potential
increases in the generation of reactive oxygen species. An endonuclease
is activated that cleaves the DNA into 180-bp fragments, destroying the
genome of the cell (Cohen and Duke 1984
,
Schwartzman and Cidlowski 1993
). Dramatic changes in the
morphology of the cell also occur due to condensation of the
cytoskeleton and inversion of the membrane lipids (Cohen and Duke 1992
, Schwartzman and Cidlowski 1993
). As
will be discussed, zinc can also induce apoptosis (Fraker and Telford 1997
, Telford and Fraker 1995
,
1998
), and it will be helpful to know whether it follows
this classic pathway of death.
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, 1992
).
However, it was suspected that zinc could inhibit other sites in the
death pathway. Indeed, zinc also binds to the vicinal cysteines in the
ligand binding region of the Gc receptor, thereby blocking the binding
of steroid both in vivo and in vitro (Telford and Fraker 1997
). Thus, zinc could block the death signal itself in such
cases. However, high levels of zinc are potentially toxic. Concerned
that such high levels of zinc could have toxic effects at later time
points, we examined the survivors of dexamethasone (Dex)-treated
cultures that were presumably "protected" by zinc (700 µmol/L).
It was found that cells thought to be protected from apoptosis by these
high levels of zinc "survived" for only a short period of time,
with ~90% being dead in a few hours (Fraker and Telford 1997
). After a 6-h exposure to 1 µmol/L Dex, thymocytes
exhibited 61% apoptosis, which was held to background levels of 16%
by both high zinc and the Gc antagonist RU38486 (Fraker and Telford 1997
). The cells were then washed free of all reagents,
recounted and placed into regular RPMI 1640 with 5% fetal bovine
serum. At 16 h after exposure to Dex, cells treated with Dex alone
or Dex plus RU38486 exhibited a viability of ~64% (Fraker and Telford 1997
). However, in Dex-treated cultures, the cells
"protected" by high zinc exhibited <5% survivors, with 95% of
the cells being in an apoptotic state. As an extra check, 700 µmol/L
Zn was added again at the 6-h mark to untreated cells, and the
Dex-plus-zinc–treated cells with losses of >80% were still noted at
16 h with no viable survivors. Thus, we found that the high
concentrations of zinc (700 µmol/L) used by previous investigators
did not provide long-term protection of cells. |
Ability of zinc to induce apoptosis |
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TOPABSTRACTLink between immune integrity...Prevalence of deficiencies in...Role of glucocorticoids in...Impact of zinc deficiency...Changes in lymphopoiesis created...Potential resistance of myeloid...Role of zinc status...Ability of zinc to...Impact of zinc supplementation...Important areas of needREFERENCES |
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).
To our surprise, zinc salts at 80–200 µmol/L added exogenously to
standard RPMI 1640 cultures for 8 h could induce 30–40%
apoptosis in thymocytes (1 µmol/L corticosterone = 60%
apoptosis) (Telford and Fraker 1995
). Cell cycle
profiles, DNA gels and phase contrast morphology all indicated that
zinc had induced a classic form of apoptosis. Moreover, the most
sensitive population was the
CD4+CD8+TCRloCD3lo
precursor T cells (47% apoptotic), where mature
CD4+CD8- and
CD4-CD8+, which express
higher levels of bcl-2, exhibited little apoptosis beyond background
levels (Telford and Fraker 1995
). Copper, iron and
nickel did not induce apoptosis, but gold, cadmium and selenium induced
necrosis. Splenic B cells (IgM+) also responded
to zinc-induced apoptosis, as did marrow B cells, with ~25%
apoptosis observed for each population (Telford and Fraker 1998
). Because these concentrations of zinc were still high, we
wanted to determine the actual intracellular levels of zinc. Atomic
absorption indicated that 6–7 ng Zn/109 cells
was all that was entering the cell in a typical 8-h experiment (1–1.5
µg Zn/109 in control cells) (Fraker and Telford 1997
, Telford and Fraker 1995
,
1998
). These concentrations are more within the realm of
physiological relevance, given recent evidence that metallothionein can
donate zinc to surrounding proteins (Maret and Vallee 1998
), along with growing evidence that there may be pools of
intracellular zinc that could provide a flux of zinc (Palmiter et al. 1996
). Future studies of modulation of cell death by zinc could lead to the identification of important new roles for zinc. Clearly, small changes in cellular zinc may play a role in the loss of precursor cells in the immune system. Perhaps suboptimal zinc and the chronic production of Gc act in synergy to heighten levels of apoptosis in precursor T and B cells as zinc deficiency advances, thereby causing lymphopenia, as discussed earlier. Likewise, cells under stress or cells in a dysregulated or an aging system may experience fluxes in zinc that might promote apoptosis.
|
Impact of zinc supplementation on immune integrity |
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TOPABSTRACTLink between immune integrity...Prevalence of deficiencies in...Role of glucocorticoids in...Impact of zinc deficiency...Changes in lymphopoiesis created...Potential resistance of myeloid...Role of zinc status...Ability of zinc to...Impact of zinc supplementation...Important areas of needREFERENCES |
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). Infants with marasmus showed weight gains and increased host defense
responses after 60 d of supplementation with 2 mg zinc (kg/d)
(Castillo-Duran et al. 1987
). Seventy-year-olds
supplemented with zinc for 1 mo had improved DTH. Despite these and
other dramatic successes, the efficacy of zinc supplementation in
reducing the impact of diseases and disease states is not being given
the priority that it deserves.
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Important areas of need |
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TOPABSTRACTLink between immune integrity...Prevalence of deficiencies in...Role of glucocorticoids in...Impact of zinc deficiency...Changes in lymphopoiesis created...Potential resistance of myeloid...Role of zinc status...Ability of zinc to...Impact of zinc supplementation...Important areas of needREFERENCES |
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With regard to the interactions between the immune system and nutrients such as zinc, the surface has been barely scratched. Most of the immunological studies performed to date have centered around the peripheral immune system. We know little about the effect of zinc deficiency and the use of zinc supplements on the mucosal immune system. Changes in gut immunology created by malnutrition no doubt contributed to the ongoing high mortality rates of children in developing nations created by infections with Escherichia coli, Salmonella, dysentery, cholera and others that create havoc in the intestine. Also, few details are known about the impact of nutritional status on pulmonary immunology and the resulting incidence of pneumonia, bronchitis, allergy or tuberculosis. We know little about the relationship of nutritional status to the acute phase response regardless of whether one considers its protective or inflammatory mode. How does suboptimal nutriture affect the fetal-neonatal immune system, and how readily is repair of immune integrity manifested when dietary status is improved? Is there a subset of elderly persons who would truly benefit from zinc supplementation, and how do we identify them? We also know little about the impact of marginal zinc status on viral or cancer defense systems. Supplementation with zinc might reduce the impact of these diseases and conditions.
Clearly, the mouse model shows that zinc is essential to lymphopoiesis and that when zinc is suboptimal, there is significant depletion of precursor lymphoid cells from the primary tissues of the immune system. The dramatic effect of zinc deficiency on marrow function is another indication of the dynamic link between immune status and zinc status. This is no doubt an underlying cause of the lymphopenia, thymic atrophy and reduced cell- and antibody-mediated responses associated with zinc deficiency. This could well be the case for PCM and other nutritional deficits and thus provides a path for others. Moreover, subsets of developing B cells in the marrow varied in sensitivity to zinc deficiency, with those expressing high levels of bcl-2 being the most resistant. This, along with other data, strongly suggests that apoptosis is one of the seminal causes of these losses. No doubt apoptosis plays a role in many of the physiological changes created by zinc deficiency. Conversely, myeloid cells in the marrow, in particular neutrophils and monocytes, exhibited substantial resistance to zinc deficiency. This is an incredible dichotomy in the effects of zinc deficiency on regulation within the marrow and is the first study to demonstrate the impact of a nutritional deficiency on marrow function. Understanding the nature of the changes in marrow function created by zinc deficiency opens the way for therapeutic intervention.
Studies also now exist that demonstrate that changes in zinc status can modulate apoptosis, providing new roles for zinc. Fluxes of zinc in the cell; synergy between zinc and Gc; and dysregulation of cellular zinc during stress, aging, autoimmune disease, ischemia, Alzheimer’s disease and others may therefore affect cell survival. Demonstration of the ability of zinc to modulate cell survival would, we hope, prompt other nutritionists to also examine the role apoptosis may play in altered growth, development, reproduction and senescence during deficiency states.
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FOOTNOTES |
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2 Supported in part by National Institutes of Health Grant DK52289.
4 Abbreviations used: AIDS, acquired immune deficiency syndrome; Dex, dexamethasone; DTH, delayed type hypersensitivity; Gc, glucocorticoid; IL-2, interleukin-2; NK, natural killer; PCM, protein-calorie deficiency
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